A novel porcine model of ataxia telangiectasia reproduces neurological features and motor deficits of human disease.

Ataxia telangiectasia (AT) is a progressive multisystem disorder caused by mutations in the AT-mutated (ATM) gene. AT is a neurodegenerative disease primarily characterized by cerebellar degeneration in children leading to motor impairment. The disease progresses with other clinical manifestations including oculocutaneous telangiectasia, immune disorders, increased susceptibly to cancer and respiratory infections. Although genetic investigations and physiological models have established the linkage of ATM with AT onset, the mechanisms linking ATM to neurodegeneration remain undetermined, hindering therapeutic development. Several murine models of AT have been successfully generated showing some of the clinical manifestations of the disease, however they do not fully recapitulate the hallmark neurological phenotype, thus highlighting the need for a more suitable animal model. We engineered a novel porcine model of AT to better phenocopy the disease and bridge the gap between human and current animal models. The initial characterization of AT pigs revealed early cerebellar lesions including loss of Purkinje cells (PCs) and altered cytoarchitecture suggesting a developmental etiology for AT and could advocate for early therapies for AT patients. In addition, similar to patients, AT pigs show growth retardation and develop motor deficit phenotypes. By using the porcine system to model human AT, we established the first animal model showing PC loss and motor features of the human disease. The novel AT pig provides new opportunities to unmask functions and roles of ATM in AT disease and in physiological conditions.

Noninvasive Transcutaneous Vagus Nerve Stimulation Decreases Whole Blood Culture-Derived Cytokines and Chemokines: A Randomized, Blinded, Healthy Control Pilot Trial.

OBJECTIVES: The purpose of this study was to test the transcutaneous noninvasive vagus nerve stimulator (nVNS) (gammaCore©) device to determine if it modulates the peripheral immune system, as has been previously published for implanted vagus nerve stimulators. MATERIALS AND METHODS: A total of 20 healthy males and females were randomized to receive either nVNS or sham stimulation (SST). All subjects underwent an initial blood draw at 8:00 am, followed by stimulation with nVNS or SST at 8:30 am. Stimulation was repeated at 12:00 pm and 6:00 pm. Additional blood samples were withdrawn 90 min and 24 hour after the first stimulation session. After samples were cultured using the Myriad RBM TruCulture (Austin, TX) system (WBCx), levels of cytokines and chemokines were measured by the Luminex assay and statistical analyses within and between groups were performed using the Wilcoxon Signed Ranks Test and Mann-Whitney U with the statistical program R. RESULTS: A significant percent decrease in the levels of the cytokine interleukin [IL]-1ß, tumor necrosis factor [TNF] levels, and chemokine, interleukin [IL]-8 IL-8, macrophage inflammatory protein [MIP]-1α, and monocyte chemoattractant protein [MCP]-1 levels was observed in the nVNS group non-lipopolysaccharide (LPS)-stimulated whole blood culture (n-WBCx) at the 24-hour time point (p < 0.05). In SST group, there was a significant percent increase in IL-8 at 90 min post-stimulation (p < 0.05). At 90 min, the nVNS group had a greater percent decrease in IL-8 concentration (p < 0.05) compared to SST group. The nVNS group had a greater percent decrease in cytokines (TNF, IL-1ß) and chemokines (MCP-1 and IL-8) at 24 hour (p < 0.05) in comparison to SST. LPS-stimulated whole blood cultures (L-WBCx) did not show a significant decrease in cytokine levels in either the nVNS or SST group across any time points. The nVNS group showed a significant percent increase in LPS-stimulated IL-10 levels at the 24-hour time point in comparison to SST. CONCLUSIONS: nVNS downregulates inflammatory cytokine release suggesting that nVNS may be an effective anti-inflammatory treatment.

Isolated lateral collateral ligament complex injury in rock climbing and Brazilian Jiu-jitsu.

We report two occurrences of high-grade tears of the lateral collateral ligament complex (LCLC), consisting of the anterolateral ligament (ALL) and fibular collateral ligament (FCL). One injury occurred in a rock climber and the other in a martial artist. Increasing awareness of isolated injuries of the LCLC will allow for appropriate diagnosis and management. We review and discuss the anatomy of the LCLC, the unique mechanism of isolated injury, as well as physical and imaging examination findings.

Twelve-month outcomes following temperature-controlled radiofrequency treatment of the septal swell body for nasal airway obstruction.

BACKGROUND: Improved nasal airway obstruction (NAO) symptoms were reported at 3 months following temperature-controlled radiofrequency (TCRF) treatment of the septal swell body (SSB). This report provides results from assessments of the long-term safety and efficacy of TCRF treatment of SSB hypertrophy to treat NAO through 12 months posttreatment. METHODS: This prospective, multicenter, long-term, open-label study was conducted in nine centers within the United States and included patients with severe/extreme NAO attributed to SSB hypertrophy. Outcome measures included assessments of Nasal Obstruction Symptom Evaluation Score (NOSE), Numeric Rating Scale (NRS) ease-of-breathing, patient satisfaction, and adverse events at 6 and 12 months. RESULTS: Of the 70 patients treated, 65 and 62 patients completed the 6- and 12-month follow-up assessments. Compared to baseline, there was a 67.5% decrease in adjusted mean NOSE scores at 6 months (mean change -49.6, 95% confidence interval [CI] -54.8 to -44.4; p < 0.001) and a 65.4% decrease at 12 months (mean change -48.1, 95% CI -53.7 to -42.5); p < 0.001), which is consistent with previously published 3-month results. A 62.0% and 62.5% improvement compared to baseline was observed in the NRS ease-of-breathing score at 6 and 12 months, respectively (p < 0.001). No serious adverse were reported overall and no new device- or procedure-related adverse events were reported in the interval between 3 and 12 months posttreatment. CONCLUSION: TCRF treatment of SSB hypertrophy has a significant and durable effect on improving the symptoms of NAO and health-related quality of life in patients with symptoms of nasal obstruction and congestion through 12 months postprocedure.

Temperature-controlled radiofrequency device treatment of septal swell bodies for nasal airway obstruction: An open-label, single arm multicenter study.

BACKGROUND: Nasal airway obstruction (NAO) is a highly prevalent disorder. Septal swell body (SSB) hypertrophy is an often overlooked contributor to NAO. SSB treatment may relieve symptoms of NAO. The objective of this study was to assess the clinical use of a temperature-controlled radiofrequency (TCRF) device to treat SSBs to improve symptoms in adults with NAO. METHODS: In this prospective, multicenter, open-label, single arm study, patients with severe or extreme NAO related to SSB hypertrophy received bilateral TCRF treatment in the SSB area. The primary endpoint was improvement in Nasal Obstruction Symptom Evaluation (NOSE) Scale scores from baseline to 3 months postprocedure. A subset of study patients underwent computed tomography (CT) imaging to evaluate posttreatment changes in SSB size. RESULTS: Mean NOSE Scale scores significantly improved from 73.5 (SD 14.2) at baseline to 27.9 (SD 17.2) at 3 months postprocedure, a reduction of -45.3 (SD 21.4, 95% confidence interval [CI]: -50.4 to -40.1; p < 0.0001); the responder rate was 95.7% (95% CI: 0.88 to 0.99; p < 0.0001). CT evaluation at 3 months showed statistically significant reductions in the SSB with the greatest reduction in the middle thickness (mean change -3.4 [SD 1.8] mL, 95% CI: -4.0 to -2.8; p < 0.0001). Minimal adverse events with any relationship to the device or procedure were reported; none were serious in nature and no septal perforations occurred. CONCLUSIONS: This study demonstrates that TCRF treatment of SSB hypertrophy is well tolerated and effective at reducing both SSB size and symptoms of NAO at 3 months posttreatment.

Structural insight into the substrate specificity of DNA Polymerase mu.

DNA polymerase mu (Pol mu) is a family X enzyme with unique substrate specificity that contributes to its specialized role in nonhomologous DNA end joining (NHEJ). To investigate Pol mu's unusual substrate specificity, we describe the 2.4 A crystal structure of the polymerase domain of murine Pol mu bound to gapped DNA with a correct dNTP at the active site. This structure reveals substrate interactions with side chains in Pol mu that differ from other family X members. For example, a single amino acid substitution, H329A, has little effect on template-dependent synthesis by Pol mu from a paired primer terminus, but it reduces both template-independent and template-dependent synthesis during NHEJ of intermediates whose 3' ends lack complementary template strand nucleotides. These results provide insight into the substrate specificity and differing functions of four closely related mammalian family X DNA polymerases.

Effects of Conformity to Masculine Norms and Coping on Health Behaviors in Men With Multiple Sclerosis.

BACKGROUND: The role of conformity to masculine gender norms in health behaviors in men with multiple sclerosis (MS) has not received attention. This cross-sectional study explores these issues and their relationship to coping and health behaviors. METHODS: Eighty-one men with MS completed the Conformity to Masculine Norms Inventory-46 and the Ways of Coping Questionnaire and provided demographic and clinical variables. These results were used to predict subscale scores of the Health Behavior Inventory-20 in multivariable regression models. RESULTS: Models for the Preventive Self-care and Avoiding Anger and Stress subscales were successfully fit. For the former, respondents endorsing lower levels of masculine conformity related to Emotional Control and higher levels of Heterosexual Self-presentation predicted greater self-care, as did higher use of Positive Reappraisal as a coping strategy. For men reporting low levels of Positive Reappraisal as a coping strategy, increasing Heterosexual Self-presentation was associated with higher levels of self-care. For those with high levels of coping with Positive Reappraisals, increased Heterosexual Self-presentation was associated with modest declines in self-care. For the Avoiding Anger and Stress subscale score, men endorsing Violence or Heterosexual Self-presentation as important aspects of masculinity also reported less efforts in controlling stress and anger. CONCLUSIONS: Masculinity adherence to traditional gender norms was a significant predictor of how men engaged in health behaviors and, in the case of Preventive Self-care, was found to interact with Positive Reappraisal as a coping strategy. Such information is novel and important to providers serving male patients with MS and can improve provider awareness/conceptualization of male patient needs.

Long-term Outcomes Following Temperature-Controlled Radiofrequency Neurolysis for the Treatment of Chronic Rhinitis.

Background: Temperature-controlled radiofrequency neurolysis of the posterior nasal nerve has been shown to reduce the symptom burden of patients with chronic rhinitis. Objectives: To evaluate the long-term safety and effectiveness of temperature-controlled radiofrequency neurolysis of the posterior nasal nerve for the treatment of chronic rhinitis. Methods: A prospective extension of a 12-month single-arm study, where reflective total nasal symptom score (rTNSS) and the responses to a study-specific quality of life questionnaire and patient satisfaction survey were collected at 24 months. Results: Forty-seven patients completed initial 12-month follow-up after treatment with the study device, of which 34 patients were reconsented and completed 24-month follow-up. The mean rTNSS of the long-term follow-up patients improved from 8.4 (95% confidence interval (CI), 7.7 to 9.0) at baseline to 2.9 (95% CI, 2.1 to 3.6), P < .001 at 24 months, a 65.5% improvement. On a 6-point scale (0-5), postnasal drip improved from a mean of 4.1 (95% CI, 3.6 to 4.6) to 2.1 (95% CI, 1.7 to 2.5) and chronic cough improved from 3.2 (95% CI, 2.7 to 3.6) to 0.9 (95% CI, 0.5 to 1.3) from baseline through 24 months; P < .001 for both measures. The proportion of patients achieving a minimal clinically important difference of 30% improvement from baseline at 24 months was 88.2% (95% CI, 73.4%-95.3%). At 24 months, 24% of patients were taking overall fewer and 15% taking overall more rhinitis medication classes than at baseline. Patients reported a higher quality of life in terms of sleep, well-being, and lower oral medication/nasal spray use at 24 months. There were no serious adverse events considered related to the procedure in the 12-24-month period. Conclusion: Temperature-controlled radiofrequency neurolysis results in a significant and durable reduction in the symptom burden of chronic rhinitis and patients reported improved quality of life through 24 months postprocedure.

Patient and Provider Insights into the Impact of Multiple Sclerosis on Mental Health: A Narrative Review.

Multiple sclerosis (MS) is a chronic disease in which the immune system attacks the central nervous system, causing inflammation and neurodegeneration. People living with MS may experience a variety of symptoms as a consequence of this process, including many "invisible" symptoms that are internally manifested and not seen by others. Of the invisible symptoms of MS, which we have reviewed in a companion article, mood and mental health disorders are of particular concern due to their high prevalence and significant impact on patient quality of life. In this review, we showcase the experiences of patient authors alongside perspectives from healthcare provider authors as we promote awareness of the common mental health conditions faced by those living with MS, such as depression, anxiety, adjustment disorder, bipolar disorder, psychosis, and suicidal ideation. Many of these conditions stem in part from the increased stress levels and the many uncertainties that come with managing life with MS, which have been exacerbated by the environment created by the coronavirus disease 2019 (COVID-19) pandemic. A patient-centered interdisciplinary approach, routine screening for mental health changes, and referral to specialists when needed can normalize discussions of mental health and increase the likelihood that people living with MS will receive the support and care they need. Management techniques such as robust social support, cognitive behavioral therapy, mindfulness-based interventions, and/or pharmacotherapy may be implemented to build resilience and promote healthy coping strategies. Increasingly, patients have access to telehealth options as well as digital apps for mental health management. Taken together, these approaches form an integrative care model in which people living with MS benefit from the care of medical professionals, a variety of support networks/resources, and self-management techniques for optimal mental health care.

Comprehensive Approach to Management of Multiple Sclerosis: Addressing Invisible Symptoms-A Narrative Review.

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system, leading to neurodegeneration and manifesting as a variety of symptoms. These can include "invisible" symptoms, not externally evident to others, such as fatigue, mood disorders, cognitive impairments, pain, bladder/bowel dysfunction, sexual dysfunction, and vision changes. Invisible symptoms are highly prevalent in people living with MS, with multifactorial etiology and potential to impact the disease course. Patient experiences of these symptoms include both physical and psychosocial elements, which when unaddressed negatively influence many aspects of quality of life and perception of health. Despite the high impact on patient lives, gaps persist in awareness and management of these hidden symptoms. The healthcare provider and patient author experiences brought together here serve to raise the profile of invisible symptoms and review strategies for a team-based approach to comprehensive MS care. We summarize the current literature regarding the prevalence and etiology of invisible symptoms to convey the high likelihood that a person living with MS will contend with one or more of these concerns. We then explore how open communication between people living with MS and their care team, stigma mitigation, and shared decision-making are key to comprehensive management of invisible symptoms. We recommend validated screening tools and technological advancements that may be incorporated into MS care to regularly monitor these symptoms, offering insight into how healthcare providers can both educate and listen to patients, with the goal of improved patient quality of life. By pairing clinical knowledge with an understanding and consideration of the patient perspective, providers will be equipped to foster a patient-centered dialogue that encourages shared decision-making. Invisible symptoms of MS.

End-bridging is required for pol mu to efficiently promote repair of noncomplementary ends by nonhomologous end joining.

DNA polymerase mu is a member of the mammalian pol X family and reduces deletion during chromosome break repair by nonhomologous end joining (NHEJ). This biological role is linked to pol mu's ability to promote NHEJ of ends with noncomplementary 3' overhangs, but questions remain regarding how it performs this role. We show here that synthesis by pol mu in this context is often rapid and, despite the absence of primer/template base-pairing, instructed by template. However, pol mu is both much less active and more prone to possible template independence in some contexts, including ends with overhangs longer than two nucleotides. Reduced activity on longer overhangs implies pol mu is less able to synthesize across longer gaps, arguing pol mu must bridge both sides of gaps between noncomplementary ends to be effective in NHEJ. Consistent with this argument, a pol mu mutant defective specifically on gapped substrates is also less active during NHEJ of noncomplementary ends both in vitro and in cells. Taken together, pol mu activity during NHEJ of noncomplementary ends can thus be primarily linked to pol mu's ability to work together with core NHEJ factors to bridge DNA ends and perform a template-dependent gap fill-in reaction.

The COVID-19 Crisis: A Mental Health Perspective and Response Using Telemedicine.

With the outbreak of COVID-19, patients and providers were forced to isolate and become innovative in ways to continue exceptional patient care. The Cleveland Clinic went from mostly in-person medical appointments to all virtual/telemedicine care in about 2 weeks' time. In this piece, we show specifically the thought process and our conversion of the Mellen Center for Multiple Sclerosis Behavioral Medicine to ensure that our patients still receive exceptional care and patient experience. Additionally, we discuss the importance of innovating the training and supervision of postdoctoral trainees using telepsychology and virtual options.

Noninvasive vagus nerve stimulation alters neural response and physiological autonomic tone to noxious thermal challenge.

The mechanisms by which noninvasive vagal nerve stimulation (nVNS) affect central and peripheral neural circuits that subserve pain and autonomic physiology are not clear, and thus remain an area of intense investigation. Effects of nVNS vs sham stimulation on subject responses to five noxious thermal stimuli (applied to left lower extremity), were measured in 30 healthy subjects (n = 15 sham and n = 15 nVNS), with fMRI and physiological galvanic skin response (GSR). With repeated noxious thermal stimuli a group × time analysis showed a significantly (p < .001) decreased response with nVNS in bilateral primary and secondary somatosensory cortices (SI and SII), left dorsoposterior insular cortex, bilateral paracentral lobule, bilateral medial dorsal thalamus, right anterior cingulate cortex, and right orbitofrontal cortex. A group × time × GSR analysis showed a significantly decreased response in the nVNS group (p < .0005) bilaterally in SI, lower and mid medullary brainstem, and inferior occipital cortex. Finally, nVNS treatment showed decreased activity in pronociceptive brainstem nuclei (e.g. the reticular nucleus and rostral ventromedial medulla) and key autonomic integration nuclei (e.g. the rostroventrolateral medulla, nucleus ambiguous, and dorsal motor nucleus of the vagus nerve). In aggregate, noninvasive vagal nerve stimulation reduced the physiological response to noxious thermal stimuli and impacted neural circuits important for pain processing and autonomic output.

Frequency and type of medication discrepancies in one tertiary care hospital.

BACKGROUND/OBJECTIVE: Discrepancies in records used within the medication use system have been identified as a contributing factor of medication errors. The objective of this study was to determine the frequency and type of discrepancies in the medication use system in one tertiary care hospital. METHODS: Using a sample of patients (convenience sampling technique), the physician's orders, the nursing medication administration record and the pharmacy profile were compared in an attempt to identify discrepancies among them. A discrepancy was defined as a deviation from the physician's order as written in the chart. Each discrepancy was categorized according to seven components of the medication order, its location in the medication use process and its mode of delivery. RESULTS: One thousand, four hundred twenty-four orders representing 197 patients from 13 nursing units were sampled for this study. Thirteen percent of the orders were discrepant and 61% of patients had at least one discrepancy. The most frequent types of discrepancies were drug omissions and unordered drugs. DISCUSSION: The discrepancies identified in this study suggest that either orders are not reaching pharmacy or orders are not being processed appropriately in pharmacy. The location of discrepancies also suggests that there are deficiencies in communication between healthcare professionals.

Posttraumatic stress disorder influences the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans.

OBJECTIVE: Although posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1ß), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNFα) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC). METHODS: After completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110min post capsaicin injection. Inflammatory (IL-1ß, IL-6, IL-8 TNFα) and anti-inflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110min. RESULTS: Following intramuscular capsaicin injection, pro-inflammatory cytokines [TNFα, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL-1ß significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70min post injection. CONCLUSION: These findings show significant central nervous system (CNS) differences in the inflammatory response to a deep pain stimulus in combat veterans with and without PTSD. They support the concept that abnormally elevated neuroinflammatory response to pain stimuli may be one CNS mechanism accounting for the high co-occurrence of PTSD and pain.

Image-guided surgery: what is the accuracy?

PURPOSE OF REVIEW: Use of image-guided surgery (IGS) systems in otolaryngology, particularly rhinology, has grown exponentially in recent years. Central to their use is the understanding of the accuracy of each system. The purpose of this review is to discuss the error inherent in all IGS systems. A standardized technique (currently used in the engineering literature) for understanding and reporting error in IGS systems is reviewed. Using this technique, the error of commercially available IGS systems is reviewed. RECENT FINDINGS: The most commonly used IGS systems depend on the conformation of the skin, as opposed to relying on bone-implanted devices. For these systems, mean accuracies 2 mm or less are routinely reported. This finding is independent of fiducial markers (eg, proprietary headsets, skin-affixed markers, or laser scanning of skin surfaces). Techniques of fiducial localization and registration of CT scans to intraoperative anatomy are proprietary to each company. As such, there is great variability in reporting system specifications-particularly error of IGS systems. This lack of standardization makes comparison of one system to another difficult if not impossible. SUMMARY: Image-guided surgery systems commonly used in rhinology report mean accuracies of 2 mm or less. Surgeons must be aware that this value represents a mean of a distribution of errors. As such, 95% of the time error can be expected to be less than approximately 1.7 times its mean value. However, outliers (errors much larger and much smaller than the mean) may exist for each IGS intervention. As noted, IGS systems function to complement-not replace-knowledge of surgical anatomy.

Cochlear implant fixation using polypropylene mesh and titanium screws.

HYPOTHESIS: Fixation of cochlear implants using prosthetic mesh is an improvement of the traditional fixation methods. STUDY DESIGN: A retrospective chart review was performed examining all adult and pediatric patients between 1998 and 2003 who underwent cochlear implantation using polypropylene mesh and titanium screws to fix the cochlear implant internal receiver. Patient age at implantation, postoperative infections, device failures, device migrations or extrusions, cerebrospinal fluid (CSF) leaks, flap complications, epidural hematoma data, and follow-up data were evaluated. RESULTS: Two hundred and eighty-five patients were identified who received cochlear implantation using the polypropylene mesh securing technique. There were five postoperative infections, two device failures, zero flap complications, zero device migrations or extrusions, zero cerebral spinal fluid leaks, and zero epidural hematomas. The two delayed device failures in this series were not related to fixation technique. CONCLUSIONS: We conclude that this technique is widely applicable, technically superior, and not associated with increased complications.

Implementation of dermato-epidemiology curriculum at Case Western Reserve University dermatology program.

Dermato-epidemiology curriculum has been identified by the American Academy of Dermatology (AAD) as an important foundation for dermatology residency training. However, no one has yet reported implementation of dermato-epidemiology curriculum. To evaluate and relate our experience carrying out a dermato-epidemiology resident education initiative, based on recommendations by the AAD Epidemiology Committee. Monthly lectures based on topics suggested by the AAD Epidemiology Curriculum. Pre- and post-test multiple choice and free-form question measures were employed to examine performance, assess resident enthusiasm, and solicit feedback from the initiative. Quantitative achievement on multiple-choice items improved slightly, but insignificantly, from 53 percent to 58 percent. Resident level of enthusiasm and perceived efficacy for the intervention varied from 3.3 to 4.0 on a 5-point Likert scale where "1" indicates strongly disagree and "5" indicates strongly agree with measures of effectiveness. Dermato-epidemiology curriculum is desirable and achievable even in dermatology programs without full-time epidemiologists. A successful epidemiology curriculum should be clinically and board-examination relevant, incorporating aspects of problem-based, interactive learning.